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Current
Gene Therapy
ISSN: 1566-5232
Current Gene Therapy
Volume 7, Number 2, April 2007
Contents
Gene Therapy for Type I Glycogen Storage Diseases
Pp. 79-88
Janice Y. Chou and Brian C. Mansfield
[Abstract]
Heme Oxygenase -1 Gene Therapy: Recent Advances
and Therapeutic Applications Pp. 89-108
Nader G. Abraham, Amit Asija, George Drummond and Stephen
Peterson
[Abstract]
Restoration of the Striatal Dopamine Synthesis for
Parkinson’s Disease: Viral Vector-Mediated Enzyme Replacement
Strategy Pp. 109-120
Thomas Carlsson, Tomas Björklund and Deniz Kirik
[Abstract]
Retinal Degenerations: From Cell Signaling to Cell
Therapy; Pre Clinical and Clinical Issues Pp. 121-129
Thérèse Cronin, Thierry Léveillard
and José-Alain Sahel
[Abstract]
Gene and Stem Cell Therapy in the Treatment of Erectile
Dysfunction and Pulmonary Hypertension; Potential Treatments
for the Common Problem of Endothelial Dysfunction Pp.
131-153
Bobby D. Nossaman, Serap Gur and Philip J. Kadowitz
[Abstract]
Abstracts
[Back to top]
Gene Therapy for Type I Glycogen Storage Diseases
Janice Y. Chou and Brian C. Mansfield
The type I glycogen storage diseases (GSD-I) are a group
of related diseases caused by a deficiency in the glucose-6-phosphatase-α
(G6Pase-α)
system, a key enzyme complex that is essential for the maintenance
of blood glucose homeostasis between meals. The complex consists
of a glucose-6-phosphate transporter (G6PT) that translocates
glucose-6-phosphate from the cytoplasm into the lumen of the
endoplasmic reticulum, and a G6Pase-α
catalytic unit that hydrolyses the glucose-6-phosphate into
glucose and phosphate. A deficiency in G6Pase-α
causes GSD type Ia (GSD-Ia) and α
deficiency in G6PT causes GSD type Ib (GSD-Ib). Both GSD-Ia
and GSD-Ib patients manifest a disturbed glucose homeostasis,
while GSD-Ib patients also suffer symptoms of neutropenia
and myeloid dysfunctions. G6Pase-α
and G6PT are both hydrophobic endoplasmic reticulum-associated
transmembrane proteins that can not expressed in soluble active
forms. Therefore protein replacement therapy of GSD-I is not
an option. Animal models of GSD-Ia and GSD-Ib that mimic the
human disorders are available. Both adenovirus- and adeno-associated
virus (AAV)-mediated gene therapies have been evaluated for
GSD-Ia in these model systems. While adenoviral therapy produces
only short term corrections and only impacts liver expression
of the gene, AAV-mediated therapy delivers the transgene to
both the liver and kidney, achieving longer term correction
of the GSD-Ia disorder, although there are substantial differences
in efficacy depending on the AAV serotype used. Gene therapy
for GSD-Ib in the animal model is still in its infancy, although
an adenoviral construct has improved the metabolic profile
and myeloid function. Taken together further refinements in
gene therapy may hold long term benefits for the treatment
of type I GSD disorders.
[Back to top]
Heme Oxygenase -1 Gene Therapy: Recent Advances
and Therapeutic Applications
Nader G. Abraham, Amit Asija, George Drummond and Stephen
Peterson
Heme oxygenase-1 (HO-1) is regarded as a sensitive and reliable
indicator of cellular oxidative stress. Studies on carbon
monoxide (CO) and bilirubin, two of the three (iron is the
third) end products of heme degradation have improved the
understanding of the protective role of HO against oxidative
injury. CO is a vasoactive molecule and bilirubin is an antioxidant,
and an increase in their production through an increase in
HO activity assists other antioxidant systems in attenuating
the overall production of reactive oxygen species (ROS), thus
facilitating cellular resistance to oxidative injury.
Gene transfer is used to insert specific genes into cells
that are either otherwise deficient in or that underexpress
the gene. Successful HO gene transfer requires two essential
elements to produce functional HO activity. Firstly, the HO
gene must be delivered in a safe vector, e.g., adenoviral,
retroviral or leptosome based vectors, currently being used
in clinical trials. Secondly, with the exception of HO gene
delivery to either ocular or cardiovascular tissue via catheter-based
delivery systems, HO delivery must be site and organ specific.
This has been achieved in rabbit ocular tissues, rat liver,
kidney and vasculature, SHR kidney, and endothelial cells
[Abraham et al., 1995a; Abraham et al.,
1995b; Abraham et al., 2002c; Quan et al.,
2004; Sabaawy et al., 2000; Sabaawy et al.,
2001; Yang et al., 2004].
In this review, we discuss the functional significance of
the HO system in various pathophysiological conditions and
the beneficial therapeutic applications of human HO gene transfer
and gene therapy in a variety of clinical circumstances.
[Back to top]
Restoration of the Striatal Dopamine Synthesis for
Parkinson’s Disease: Viral Vector-Mediated Enzyme Replacement
Strategy
Thomas Carlsson, Tomas Björklund and Deniz Kirik
Parkinson’s disease is the second most common neurodegenerative
disease. It is charaterized by a progressive loss of dopamine
(DA) producing neurons in the midbrain, which result in a
decline of DA innervations present in the forebrain, in particular,
the striatum. The disease leads to appearance of motor symptoms
involving akinesia/bradykinesia, gait disturbances, postural
imbalance and tremor. Oral administration of L-3,4-dihydroxyphenylalanine
(L-DOPA), the precursor of DA, provides very good symptomatic
relief, but this intermittent and pharmacological treatment
is compromised by severe side effects, such as the appearance
of abnormal involuntary movements. Viral vector-mediated direct
gene transfer techniques are currently being explored in order
to provide continuous and stable synthesis of DA in the brain.
This review focuses on the basic idea of DA replacement, first
describing the enzymatic machinery important for DA synthesis
and secondly the various alternative strategies pursued in
several laboratories. The DOPA delivery strategy,
based on the co-transduction of tyrosine hydroxylase (TH),
and GTP cyclohydrolase 1 (GCH1) genes, has been shown to be
a powerful approach providing a robust behavioral recovery
and reversal of side effects of the pulsatile administration
of L-DOPA medication. The DA delivery strategy, on
the other hand, aims at triple transduction of the TH, GCH1
and aromatic amino-acid decarboxylase (AADC) enzymes, and
thereby provide a higher rate of conversion of DOPA to DA.
Finally, transduction of AADC alone has been proposed as a
means to improve the conversion of peripherally administered
L-DOPA. As the basic scientific rationale behind these strategies
are well understood and the results of the animal experiments
are very encouraging, we are now entering into an exciting
phase with increasing momentum toward the first clinical applications
using this experimental therapy in patients suffering from
PD.
[Back to top]
Retinal Degenerations: From Cell Signaling to Cell
Therapy; Pre Clinical and Clinical Issues
Thérèse Cronin, Thierry Léveillard
and José-Alain Sahel
Extracellular signaling molecules have been implicated in
the progression of Retinal Degeneration (RD). Gene regulatory
events linked to the maintenance of retinal structure and
function incorporate signaling cascades that may serve as
therapeutic targets for some forms of blindness. This review
shall focus on the evidence for non-cell-autonomous mechanisms
that affect the pattern of degeneration seen in retinal dystrophies,
the types of signals that may influence the course of degeneration
and finally with the related prospects for retinal-therapies.
[Back to top]
Gene and Stem Cell Therapy in the Treatment of Erectile
Dysfunction and Pulmonary Hypertension; Potential Treatments
for the Common Problem of Endothelial Dysfunction
Bobby D. Nossaman, Serap Gur and Philip J. Kadowitz
The endothelium has an important regulatory role
in the maintenance of vascular homeostasis, vascular tone,
blood flow, and in preserving a non-thrombogenic blood-tissue
interface. Injury to the vascular wall with subsequent endothelial
dysfunction alters these important regulatory functions leading
to a state of abnormal endothelial function. In this paper,
we review the pathophysiology of endothelial dysfunction and
how this disorder is common to the development of erectile
dysfunction and of pulmonary arterial hypertension. Current
medical therapies for these two disorders are discussed followed
by a review of the preclinical studies involving currently
available strategies for gene and stem cell therapy and their
potential for the clinical treatment of these two disorders
of endothelial dysfunction.
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